Patient-Derived Human Induced Pluripotent Stem Cells for Diabetes Cell Replacement Therapy and Drug Screening

Patient-derived induced pluripotent stem (iPS) cells, differentiated to disease-relevant cells, are becoming quite important for the study of diseases due to their potential for cell replacement therapy and drug screening as well as improving our understanding of the disease pathophysiology. In Type 1 diabetes (T1D), pancreatic insulin-producing β cells are destroyed by an autoimmune attack and are not normally available for study, particularly without having undergone any disease-related stress. We have developed a strategy to generate stem cell-derived-β cells (SC-β cells) from iPS cells derived from T1D patients (T1D SC-β cells). This method utilizes three-dimensional cellular aggregates grown in suspension culture within spinner flasks and can produce up to half a billion cells per production run. These cells are able to function both in vitro and in vivo, have incredibly similar gene expression compared to isolated cadaveric β cells, and package their insulin into dense granules. When transplanted into mice that have had their own endogenous β cells destroyed with Alloxan, T1D SC-β cells can prevent diabetes and control blood glucose. Furthermore, we have developed an in vitro disease model of β cell stress using cytokine treatment, demonstrated partial rescue of this phenotype with an Alk5 inhibitor, and demonstrated that these cells respond to several different categories of anti-diabetic drugs. T1D SC-β cells have value in disease modeling and drug screening applications and, combined with autoimmune-modulating therapies, in cell replacement therapy.